The introduction of protease-inhibitor based antiretroviral therapy (PI-ART) has reduced the mortality associated with HIV infection (HIV+). Unfortunately, PI-ART use is a major risk factor for insulin resistance, an important risk factor fr diabetes and coronary heart disease (CHD). Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile salt, improves insulin sensitivity in insulin resistant people who do not have HIV. We have found that TUDCA markedly ameliorates ritonavir-induced insulin resistance in human myotubes and mice. The mechanism(s) responsible for these TUDCA-induced metabolic improvements are unclear, but could be related to: 1) TGR5 receptor activation, which upregulates cellular factors in muscle, including type 2 deiodinase (which increases intracellular triiodothryonine) and PGC-1 that increase mitochondrial biogenesis and fatty acid oxidation and/or 2) acting as chaperones that reduce endoplasmic reticulum (ER) stress by assisting protein folding. Initiation of ritonavir-boosted PI-ART worsens insulin sensitivity in HIV+ people and induces markers of ER stress in adipose tissue. We propose to perform a double-blind, randomized, controlled trial to determine if TUDCA improves insulin sensitivity in insulin-resistant, HIV+ people receiving PI-ART and to clarify the molecular mechanisms responsible for these improvements. We will randomly assign 48 insulin- resistant, HIV+ subjects to either placebo or TUDCA (1.75g/day x 30 days) and will measure multi-organ insulin sensitivity before and after the intervention by using a multistage hyperinsulinemic euglycemic clamp with infusion of stable isotope labeled tracers. To clarify the mechanisms responsible for the anticipated improvements in insulin sensitivity, we will examine the effect of TUDCA on TGR5 activation (type 2 deiodinase expression) in skeletal muscle biopsies and on ER stress by measuring Grp78 in adipose tissue biopsies taken before and after TUDCA administration. The results from this study will determine not only whether TUDCA may be effective for treatment of PI-associated insulin resistance but is also expected to identify new pathways by which TUDCA exerts insulin sensitizing effects. In addition to improving clinical care of people with HIV, the findings of this study may allow development of new drugs for treatment of type 2 diabetes.